DESCRIPTION: Central nervous system (CNS) disease remains a pressing problem in the HIV pandemic despite the introduction of combination antiretroviral therapy (cART). The abuse of stimulants such as methamphetamine (METH) is believed to exacerbate the deleterious effects of HIV infection. While the introduction of cART has greatly reduced neurodegeneration and improved neurocognitive outcomes, antiretrovirals may themselves be neurotoxic. The overarching hypothesis behind the present project is that understanding the dysregulations of the gene regulatory network that underlie the effects of HIV and METH abuse in the cART setting and their detrimental interactions, will elucidate key molecular mechanisms driving pathologic phenotypes, such as cognitive impairment and compulsivity to take METH, and indicate potential targets for future therapies. To this end, we propose to use a validated systems biology strategy for the reconstruction and interrogation of genome-wide gene regulatory networks in conjunction with high-throughput sequencing, HIV-1 transgenic (Tg) rats, and a state-of-the-art paradigm of voluntary intravenous drug self-administration under long access (LgA) conditions, which leads to compulsive (dependent) METH intake, and short access (ShA) conditions, which is characterized by a non-dependent, more recreational pattern of METH use. In particular, we will reconstruct a multidimensional genome-wide regulatory model (interactome) integrating multiple levels of gene expression regulation including the transcriptional (mRNA), post-transcriptional (miRNA) and post-translational (inferred protein-protein interactions and modulators of transcription factor activity) levels. We will interrogate the interactome to identify the gene network dysregulations associated with the effects of HIV, compulsive METH use, the detrimental effects of cART and their interactions. In preliminary studies with this systems biology approach, we interrogated a human prefrontal cortex interactome with gene expression profiles from HIV patients of the National NeuroAIDS Tissue Consortium (NNTC) and HIV-1 Tg rats, and identified candidate molecular mechanisms driving the reduced trophic support and mitochondrial dysfunction associated with neurodegeneration in HIV patients, which are not easily inferred by conventional high-throughput analysis methods. Interactome reconstruction and interrogation will be integrated with behavioral analysis and neuropathology to phenotypically validate the role of key genes responsible for the effects of HIV, METH and cART on cognition, compulsivity, depression-like state, and neurodegeneration. Ultimately this proposal - at the interface of computational analysis of gene network regulation and advanced behavioral pharmacology - is aimed at identifying new testable mechanistic hypotheses that may lead to transformative new therapeutic concepts to improve neuropsychological functioning in people with HIV.